Geographic variation in the aetiology, epidemiology and microbiology of bronchiectasis

Bronchiectasis is a disease associated with chronic progressive and irreversible dilatation of the bronchi and is characterised by chronic infection and associated inflammation. The prevalence of bronchiectasis is age-related and there is some geographical variation in incidence, prevalence and clinical features. Most bronchiectasis is reported to be idiopathic however post-infectious aetiologies dominate across Asia especially secondary to tuberculosis. Most focus to date has been on the study of airway bacteria, both as colonisers and causes of exacerbations. Modern molecular technologies including next generation sequencing (NGS) have become invaluable tools to identify microorganisms directly from sputum and which are difficult to culture using traditional agar based methods. These have provided important insight into our understanding of emerging pathogens in the airways of people with bronchiectasis and the geographical differences that occur. The contribution of the lung microbiome, its ethnic variation, and subsequent roles in disease progression and response to therapy across geographic regions warrant further investigation. This review summarises the known geographical differences in the aetiology, epidemiology and microbiology of bronchiectasis. Further, we highlight the opportunities offered by emerging molecular technologies such as -omics to further dissect out important ethnic differences in the prognosis and management of bronchiectasis.NMRC (Natl Medical Research Council, S’pore)MOH (Min. of Health, S’pore)Published versio

A statin-dependent QTL for GATM expression is associated with statin-induced myopathy

Statins are widely prescribed for lowering plasma low-density lipoprotein (LDL) concentrations and cardiovascular disease risk(1), but there is considerable interindividual variation in treatment response(2,3) and increasing concern regarding the potential for adverse effects, including myopathy(4) and type 2 diabetes(5). Despite evidence for substantial genetic influence on LDL concentrations(6), pharmacogenomic trials have failed to identify genetic variations with large effects on either statin efficacy(7-9) or toxicity(10), and have yielded little information regarding mechanisms that modulate statin response. Here we identify a downstream target of statin treatment by screening for the effects of in vitro statin exposure on genetic associations with gene expression levels in lymphoblastoid cell lines derived from 480 participants of a clinical trial of simvastatin treatment(7). This analysis identified six expression quantitative trait loci (eQTLs) that interacted with simvastatin exposure including rs9806699, a cis-eQTL for the gene GATM that encodes glycine amidinotransferase, a rate-limiting enzyme in creatine synthesis. We found this locus to be associated with incidence of statin-induced myotoxicity in two separate populations (meta-analysis odds ratio = 0.60, 95% confidence interval = 0.45-0.81, P=6.0×10(-4)). Furthermore, we found that GATM knockdown in hepatocyte-derived cell lines attenuated transcriptional response to sterol depletion, demonstrating that GATM may act as a functional link between statin-mediated cholesterol lowering and susceptibility to statin-induced myopathy